Lipid nanoparticle-mediated mRNA/siRNA dual-bioengineered dendritic cell vaccines combined of PD-1/PD-L1 blockade for
Dong Yang1, Jing Zhan1, Ling Miao1
1Department of Gastroenterology, The First Hospital of Jilin University, Changchun, Jilin, 130021, China.
Abstract:
DC vaccines occupy a pivotal position in the realm of cancer treatment, leveraging the immune system to precisely target and effectively eliminate tumor cells. However, current challenges in tumor DC vaccine development include issues such as limited efficacy and potential upregulation of immunosuppressive molecules like PD-L1 on tumor cells. Herein, we employed microfluidic technology to fabricate lipid nanoparticles (LNPs) that simultaneously encapsulate OVA mRNA (mOVA), encoding the model antigen OVA, and siRNA targeting PD-L1. The LNP/mOVA/siPD-L1 nanoparticles were utilized to transfect bone marrow-derived dendritic cells (BMDCs) to construct dual-bioengineered DC vaccines. Subsequently, the efficacy of the dually bioengineered DC vaccines was verified in both prophylactic and therapeutic tumor vaccine models. The upregulation of PD-L1 protein expression on the surface of tumor cells was further blocked by combination of anti-PD-L1 antibody therapy. Notably, the combined therapy achieved complete tumor suppression and the rechallenge experiments demonstrated the tumor immune memory effect induced by the combined therapy, highlighting its potential to elicit long-lasting immunity against cancer. Overall, our findings suggest that this combined therapy holds significant promise for the treatment, metastasis prevention, and recurrence management of tumors, with potential clinical application value in the future.
Insights
This study developed dual-bioengineered dendritic cell (DC) vaccines using microfluidic technology to enhance cancer treatment. The combined therapy achieved complete tumor suppression and long-lasting immune memory.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Dendritic cell (DC) vaccines are crucial for cancer immunotherapy but face challenges like limited efficacy and immunosuppression.
- Tumor cells can express Programmed Death-Ligand 1 (PD-L1), inhibiting anti-tumor immune responses.
Purpose of the Study:
- To develop dual-bioengineered DC vaccines encapsulating mRNA for a model antigen and siRNA targeting PD-L1.
- To evaluate the efficacy of these DC vaccines in combination with anti-PD-L1 antibody therapy in preclinical tumor models.
Main Methods:
- Microfluidic technology was used to fabricate lipid nanoparticles (LNPs) co-delivering mRNA and siRNA.
- Bone marrow-derived dendritic cells (BMDCs) were transfected with LNP/mOVA/siPD-L1 to create dual-bioengineered DC vaccines.
- Therapeutic and prophylactic tumor models were used to assess vaccine efficacy and immune memory.
Main Results:
- The dual-bioengineered DC vaccines, combined with anti-PD-L1 antibody therapy, led to complete tumor suppression.
- This combination therapy effectively blocked PD-L1 expression on tumor cells.
- Rechallenge experiments confirmed the induction of a robust and long-lasting tumor immune memory response.
Conclusions:
- Dual-bioengineered DC vaccines combined with anti-PD-L1 blockade show significant promise for cancer treatment, metastasis prevention, and recurrence management.
- This approach has potential for future clinical applications in oncology.
- The study highlights the potential for eliciting durable anti-tumor immunity.
